| چکیده انگلیسی مقاله |
As one of the hot topics in the epigenetic studies, histone deacetylases inhibitors (HDACIs) have been introduced to treat a variety of diseases such as cancer, immune disorder and neuronal diseases [1]. Due to their effective roles in the onset of cancer and its progression, HDAC Class I isoforms (HDAC 1, 2, 3 and 8) were considered in this study. Herein, our objective is to determine the important isoform-selective and isoform-active structural features of HDACIs using the valid classification models. For this purpose, five datasets including 8224 molecules of HDAC1, HDAC2, HDAC3, and HDAC8 together with their corresponding biological activity (in terms of IC50 (nM)) were collected from the Binding Database. Five classification models based on Support vector machine (SVM), and Supervised Kohonen network (SKN) methods were established to identify key features of isoform-selective and isoform-active HDACIs. The variable importance in projection (VIP) [2] method was used to select the suitable set of molecular descriptors from 3224 molecular descriptors that were calculated by DRAGON software ver. 5. The statistical evaluation of the developed classification models was implemented by parameters derived from confusion matrix. The descriptor analysis show that physicochemical properties, such as hydrogen bonding, number of branches, size, flexibility, polarity and sphericity in the structure of molecules, were closely related to the bioactivity of HDACIs. The reliability and predictive ability of the conducted models were evaluated using the tenfold cross-validation techniques, test sets and applicability domain analysis. All of the obtained classification models represented high statistical quality and predictive ability with accuracy greater than 85% for the test sets. The proposed strategy and the selective patterns represented in this paper can be applied by researchers in the pharmaceutical sciences who aim to use the same idea for the design of drugs with improved anticancer properties. |
